Thrombolytic therapy of myocardial infarction is an effective, medically well tested and proven therapy for the removal of occlusive thrombi in the coronary arteries of the heart. Recombinant human t-PA (tissue-type plasminogen activator) produced by DNA technology in accordance with U.S. Pat. No. 4,766,075 has proven to be effective for the dissolution of coronary thrombi (Verstraete et al., Lancet II, 1985; 965-969). By early lysis therapy of the myocardial infarction the residual heart function after myocardial infarction can be improved in comparison with other therapies (Armstrong et al., J. Am. Coll. Cardiol., 1989; 13: 1469-1476) and a higher survival rate can be achieved in comparison with other therapies (Wilcox et al., Lancet II, 1988; 525-539).
Large thrombolysis studies with, in all, several thousand patients show that rapid induction of thrombolysis with early reperfusion of the myocardial tissue leads to rescue of myocardial tissue and thus to an increase of survival rate (GISSI study group, Lancet I, 1986; 397-401). For this reason, it is necessary to induce thrombolytic therapy at a point of time at which the tissue lying behind the coronary occlusion is not yet irreversibly damaged.
In principle, in the case of the treatment of a coronary occlusion, the problem exists of avoiding reocclusion of the infarcted blood vessel after successful initial thrombolysis. This disadvantageous effect has been observed for recombinant wild type t-PA (e.g., Alteplase) (Cheseboro et al., Circulation, 1987; 76: 142-154). The reocclusion of the infarcted blood vessel leads to increased morbidity and mortality. For the prevention of reocclusions, substances are used of differing pharmacological working principles, such as heparin (Bleich et al., Am. J. Cardiol., 1990; 66: 1412-1417) and acetylsalicylic acid (Hsia et al., N. Engl. J. Med. 1990: 323: 1433-1437). The prolonged infusion of recombinant wild type t-PA (Alteplase) is also said to prevent the reocclusion of the infarcted blood vessel due to a longer period of thrombolysis (Gold et al., Circulation, 1986: 73: 347-352; Verstraete et al., Am. J. Cardiol. 1987; 60: 231-237; Johns et al., Circulation, 1988; 78: 546-556). However, after ending of the infusion, the appearance of reocclusions is frequently observed.
Human tissue plasminogen activator, produced by recombinant DNA technology ("rt-PA") has already been administered as double or multiple boli to a few patients in the scope of clinical preliminary investigations. Admittedly, high dissolution rates of the thrombi were found up to 90 minutes after the administration of the first bolus but, because of the high doses, extensive, systemic plasminogen activation with subsequent almost complete reduction of fibrinogen was observed (only 15.5 to 5.2% of the initial value) (J. Am. Coll. Cardiol. 1991 (17(2), 152A). Undesired reduction of fibrinogen levels represents a disadvantage in that during emergency operations, since there is a high tendency to hemorrhage, intensive supervision of the patient is necessary. Further, in the case of double and triple bolus administration of rt-PA, a tendency to reocclude was observed in the blood vessels (Circulation, 1990, 82(4), Suppl. III, 538, abstract 2137; Br. J. Haematol. 1991, 77, Suppl. 1, 47, abstract P080). A study was also carried out for Alteplase in which multiple bolus administration was investigated in more detail (Coronary Artery Disease, 1990, 1(1), 83-88). The study concluded that single bolus administration was preferred.
Because of the above-mentioned disadvantageous effects, administration of rt-PA in the form of a double or multiple bolus has found no practical use. Furthermore, the bolus administration of rt-PA has been regarded as being inexpedient from the fact that the half life of rt-PA is relatively short and only amounts to 3-6 minutes (Garabedian et al., J. Am. Coll. Cardiol. 1987; 9: 599-607). This means that, to ensure thrombolytic efficacy, relatively long-lasting infusion is necessary for the maintenance of effective plasma levels. However, in emergency situations the long-lasting infusion of r-tPA (30 minutes to 6 hours) represents a distinct treatment disadvantage. Furthermore, this leads to increased risk of hemorrhages (Marder and Sherry, N. Engl. J. Med. 1988; 318: 1512-1520).
surprisingly, it has now been found that thrombolytically active proteins, preferably those with a half life longer than that of rt-PA can be used successfully in the treatment of coronary occlusions, when the proteins used are administered in the form of a fractionated administration of two or more bolus injections. Also, all thrombolytically active proteins, when combined with heparin can be used in the multiple bolus system described herein. In this way, rapid and simple administration of thrombolytically active proteins for the effective treatment of thromboembolic diseases by, e.g., inhibiting reocclusion rate, is made possible.